Influenza A viruses are a major global health concern. Despite annual vaccination programs in the US, 10-15% of the population is infected annually accounting for an estimated 36,000 deaths and 200,000 hospitalizations. Two classes of antiviral drugs have been approved for influenza prophylaxis and treatment. Alarmingly, the past decade has witnessed the emergence of drug-resistant as well as novel 2009 pandemic (H1N1) and highly pathogenic (H5N1) strains of influenza A. Amantadine-resistance has become so widespread the adamantanes have become all but ineffective. Significant resistance to neuraminidase inhibitors has also been observed in some influenza A strains. Thus, there is an urgent need for new and more effective antiviral therapies. Optimally, as adopted for the treatment of other viral diseases, combination drug therapies would be used to provide the most effective prophylaxis and treatment and to inhibit the emergence of drug-resistance. Here we propose to optimize potency and cytotoxicity properties of identified novel hit series compounds that overcome current drug-resistance mechanisms to inhibit both amantadine-sensitive and -resistant forms of the M2 proton channel. Optimization of these chemical series could provide novel broad-spectrum therapeutics for new mono- and combination antiviral drug therapies for influenza A; a designated NIAID high priority area of interest.